RESUMEN
A fatal case following ehtyleneimine inhalation is described. Profound destructive effects on tracheobronchial cartilage were found at necropsy after an interval of apparent recovery from early phases of poisoning. The pathogenesis of these cartilaginous changes is discussed. It is proposed that they may have been due to proteases liberated from liberated from mucosal granulation tissue.
Asunto(s)
Bronquios/patología , Iminas/envenenamiento , Edema Pulmonar/inducido químicamente , Tráquea/patología , Animales , Autopsia , Espasmo Bronquial/inducido químicamente , Cartílago/patología , Endoscopía , Etilenos/envenenamiento , Etilenos/toxicidad , Granuloma/inducido químicamente , Cobayas , Humanos , Hidrocortisona/uso terapéutico , Masculino , Persona de Mediana Edad , Edema Pulmonar/patología , Conejos , Ratas , Recurrencia , Estenosis Traqueal/inducido químicamente , TraqueotomíaAsunto(s)
Acetaminofén/envenenamiento , Sobredosis de Droga/tratamiento farmacológico , Acetaminofén/sangre , Benzoquinonas/envenenamiento , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Inhibidores del Citocromo P-450 CYP2E1/uso terapéutico , Fomepizol , Humanos , Iminas/envenenamiento , Hígado/efectos de los fármacos , Hígado/patología , Pirazoles/uso terapéuticoRESUMEN
Although acetaminophen is the most widely used analgesic in the world, it is also a leading cause of toxic drug overdoses. Beyond normal therapeutic doses, the drug is hepatotoxic and genotoxic. All of the harmful effects of acetaminophen have been attributed to the production of its toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Since many of the cytotoxic/genotoxic events triggered by NAPQI are consistent with the actions of topoisomerase II-targeted drugs, the effects of this metabolite on human topoisomerase IIalpha were examined. NAPQI was a strong topoisomerase II poison and increased levels of enzyme-mediated DNA cleavage >5-fold at 100 microM. The compound induced scission at a number of DNA sites that were similar to those observed in the presence of the topoisomerase II-targeted anticancer drug etoposide; however, the relative site utilization differed. NAPQI strongly impaired the ability of topoisomerase IIalpha to reseal cleaved DNA molecules, suggesting that inhibition of DNA religation is the primary mechanism underlying cleavage enhancement. In addition to its effects in purified systems, NAPQI appeared to increase levels of DNA scission mediated by human topoisomerase IIalpha in cultured CEM leukemia cells. In contrast, acetaminophen did not significantly affect the DNA cleavage activity of the human enzyme in vitro or in cultured CEM cells. Furthermore, the analgesic did not interfere with the actions of etoposide against the type II enzyme. These results suggest that at least some of the cytotoxic/genotoxic effects caused by acetaminophen overdose may be mediated by the actions of NAPQI as a topoisomerase II poison.